The experience-dependent modifications of functional synaptic connections in the brain constitute a cellular mechanism underlying certain forms of learning and memory acquisition. If memory formation depends on the strengthening synaptic connections through LTP, then LTD and depotentiation are thought to be needed to decrease synaptic efficacy and reset the synapse to a basal state. This scenario allows the brain to avoid eventual saturation of information storage as a result of memory formation. Here we propose a combined electrophysiological and biochemical study to address several specific questions concerning the basic cellular and molecular mechanisms underlying induction and expression of LTD and depotentiation in the CA1 region of the hippocampus. In Aim 1, we will characterize the synaptic mechanisms of LTD and depotentiation. We have preliminary data indicating that depotentiation of L-LTP at the level of unitary EPSCs can be induced by low frequency stimulation. We propose to use such unitary recordings in an analysis of the synaptic mechanisms of LTD and depotentiation. Minimizing quantal variance by assaying release from a limited number of release sites, we will be able to directly assess how LTD or depotentiation change quantal parameters of synaptic transmission at CA3-CA1 synapses. In Aim 2, we will characterize the induction mechanisms of depotentiation of late LTP. By investigating these mechanisms and comparing them to the induction mechanisms of LTD that have been extensively studied, we will address a question whether depotentiation induced late after LTP onset and LTD involve the same induction mechanisms. In Aim 3, we will explore the downstream signaling mechanisms of depotentiation of late LTP. By combining electrophysiological, biochemical and genetic approaches, we will illuminate some of the biochemical steps underlying this type of depotentiation. This will enable us to elucidate a question whether LTD and depotentiation of L-LTP operate through identical or different signaling mechanisms. These experiments will improve our understanding of the cellular mechanisms of synaptic plasticity in the mammalian hippocampus. A better understanding of the basic mechanisms of synaptic plasticity will permit the rational development of better therapeutics treatments of the memory disorders. [unreadable] [unreadable]